Studies of limitin for prevention of bone resorption in bacterial periodontitis

限制素预防细菌性牙周炎骨吸收的研究

• 批准号: 16591836
• 负责人: SATO Takuya
• 金额: $ 2.24万
• 依托单位: Meikai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591836/
• 关键词: limitin; osteoclasts; periodontitis; bone resorption; B細胞

Periodontitis is a bacterial disease and causes tooth loss due to alveolar bone resorption. Immunological reaction due to periodontitis, that is necessary for prevention of systemic infection of the bacteria, results in excessive osteoclastogenesis. Therefore, it is important for treatment of periodontitis to inhibit osteoclastogenesis without diminishing immunological reactions. Limitin is a type-I interferon (IFN) like cytokine and known to stimulate immune responses. Since the other type-I IFN, IFN-beta, inhibits osteoclastogenesis, I hypothesized that limitin also could prevent osteoclastogenesis with stimulatory effects on immune systems. In this project, I studied the effects of limitin on osteoclastogenesis and the mechanism of the effects. I found that limitin strongly inhibits osteoclastogenesis in vitro cultures. On the other hand, limitin stimulated productions of inflammatory cytokines, such as TNF-alpha and RANKL, by CD3-activated T cells. When explored the mechanism of the inhibitory effect of limitin on osteoclastogenesis, I found that limitin decreases c-fos content in osteoclast precursors and stimulates PKR mRNA expression, which is known to be up-regulated in virul infection and to inhibit protein synthesis. Limitin also inhibited transcription of NFATc1 that is a master gene of osteoclastogenesis and is activated by a combination of transcription factors including c-fos. When PKR mRNA was decreased by siRNA technique, limitin did not diminished c-fos content and osteoclastogenesis. These data suggest that limitin inhibits osteoclastogenesis via PKR-dependent inhibition of c-fos synthesis. Limitin is a potential therapeutic factor for prevention of bone loss in periodontal diseases.

牙周炎是一种细菌疾病，由于肺泡骨吸收导致牙齿脱落。由于牙周炎引起的免疫反应，这是预防细菌全身感染所必需的，导致过度骨质核层生成。因此，对于牙周炎的治疗以抑制破骨细胞生成而不减少免疫反应，这一点很重要。极限蛋白是I型干扰素（IFN），例如细胞因子，已知可刺激免疫反应。由于另一种IFN IFN IFN-β抑制了破骨构成的发生，因此我假设极限蛋白也可以防止破骨细胞生成，从而对免疫系统产生刺激作用。在这个项目中，我研究了极限素对破骨细胞生成的影响和作用的机理。我发现，限制在体外培养物中强烈抑制破骨细胞生成。另一方面，通过CD3激活的T细胞，极限刺激炎性细胞因子（例如TNF-Alpha和RankL）的生产。当探索极限蛋白对破骨细胞生成的抑制作用的机制时，我发现极限蛋白会降低破骨细胞前体中的C-FOS含量并刺激PKR mRNA表达，已知在VIRUL感染中已上调并抑制蛋白质合成。极限蛋白还抑制了NFATC1的转录，该转录是破骨细胞生成的主要基因，并通过包括C-FOS在内的转录因子的组合而激活。当通过siRNA技术降低PKR mRNA时，极限蛋白不会降低C-FOS含量和破骨细胞生成。这些数据表明，极限素通过PKR依赖性抑制C-FOS合成抑制破骨细胞的发生。极限素是预防牙周疾病骨质流失的潜在治疗因素。